Dysregulation of the RAS-MAPK signalling pathway has recently been recognized as the molecular cause underlying a group of clinically related developmental disorders with features including reduced postnatal growth, facial dysmorphism, cardiac defects, ectodermal anomalies, variable cognitive deficits and susceptibility to certain malignancies8,9. These Mendelian traits, including Noonan, LEOPARD, cardiofaciocutaneous and Costello syndromes, neurofibromatosis type 1 and related phenotypes, are caused by mutations in genes encoding RAS proteins (KRAS and HRAS), downstream transducers (RAF1, BRAF, MEK1 and MEK2), or pathway regulators (PTPN11, SOS1, NF1 and SPRED1). For Noonan syndrome (NS), the most common of these disorders (1:2500 live births), mutations are observed in several of these RAS-MAPK signalling pathway genes, constituting approximately 70% of cases.
Noonan syndrome (NS) is an autosomal dominant, pleiomorphic disorder characterized by short stature, facial dysmorphia, congenital heart defects (e.g., most commonly pulmonic stenosis and hypertrophic cardiomyopathy) and skeletal anomalies (Noonan, Am. J. Dis. Child. 116:373-80, 1968; Allanson, J. Med. Genet. 24:9-13, 1987). Other frequently associated disorders include a webbed neck, chest deformities, cryptorchidism, mental retardation, and bleeding diatheses. NS is a relatively common syndrome with an estimated incidence of 1:1000 to 1:2500 live births. The disorder is genetically heterogeneous and previously identified genes account for approximately only 65% of cases. In addition, there are some closely related disorders, such as Noonan-like syndrome with loose anagen hair, that are difficult to discern, particularly in infants and young children.
Noonan-like syndrome with loose anagen hair refers to disorders described under Online Mendelian Inheritance in Man database of John Hopkins University Accession No. OMIM 607721. Commonly, Noonan-like syndrome with loose anagen hair is characterized by one or more of the following phenotypic features: short stature, certain facial phenotype including high forehead, hypertelorism, palpebral ptosis and low-set and posteriorly rotated ears, macrocephaly, enlarged cerebral spinal fluid spaces, short neck with redundant skin, severe growth hormone (GH) deficiency, mild psychomotor delay with attention deficit/hyperactivity disorder (ADHD), mild dilatation of the pulmonary root, ectodermal abnormalities such as ichthyosis, darkly pigmented and hairless skin, and the unusual aspect of the hair, defined as loose anagen hair syndrome. Reviewed in Mazzanti et al., Am J Med Genet A. 2003, 118A:279-286.
The clinical diagnosis of NS and related disorders such as Noonan-like syndrome with loose anagen hair depends on recognition of the symptoms by a knowledgeable doctor. Nevertheless, substantial phenotypic variations, including mild or subtle cases, make the diagnosis difficult. Furthermore, the facial characteristics become less apparent with progressing age, so the condition will sometimes remain undiagnosed. No genetic test is currently available for diagnosing Noonan-like syndrome with loose anagen hair. Furthermore, currently available genetic tests for diagnosing NS (detecting mutations in PTPN11 and KRAS) account for only 50% of patients suspected of having NS. Therefore, there remains a great need for more specific (e.g., genetic) diagnostics of Noonan-like syndrome with loose anagen hair and other NS-related diseases.